Forms A and B of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl ]thio]ethyl]ami no]methylene]-4-bromo-benzenesulfonamide

ABSTRACT

PCT No. PCT/ES94/00109 Sec. 371 Date Jul. 3, 1996 Sec. 102(e) Date Jul. 3, 1996 PCT Filed Nov. 4, 1994 PCT Pub. No. WO96/14306 PCT Pub. Date May 17, 1996Two forms of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamidehave been identified. A process for the preparation of thereof and the use thereof are described.

The present invention relates to novel Forms A and B of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]]amino]methylene]-4-bromo-benzenesulfonamide-compound known as ebrotidine (WHO).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an infrared (IR) spectrum of ebrotidine Form A.

FIG. 2 is an X-ray powder diffractogram of

a) Ebrotidine Form A.

b) Ebrotidine Form B.

FIG. 3 is a differential scanning calorimetry (DSC) thermogram of Ebrotidine Form A.

FIG. 4 is a infrared (IR) spectrum of Ebrotidine Form B.

FIG. 5 is a differential scanning calorimetry (DSC) thermogram of Ebrotidine Form B.

DETAILED DESCRIPTION OF THE INVENTION

N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromobenzenesulfonamide, ebrotidine, is a compound which is active as a histamine H₂ -receptor antagonist, thus becoming useful in therapy as an acid secretion inhibitor. The preparation of this compound was disclosed in European Patent No. 0159012 and U.S. Pat. No. 4728655. The applicants have found out that ebrotidine exhibits two novel forms, A and B, having a melting point in the range of 74-78° C. and 142.5-146° C. respectively. The present invention provides a process for obtaining selectively Forms A and B of ebrotidine. In the aforesaid patents, ebrotidine was obtained with a melting point of 107-110° C. By performing the same experimental method in those patents (Example 23 in both of them), the applicants have found out in the course of different crystallization assays that if to the methanol filtrate resulting from the reaction between [4-[[(2-aminoethyl)thio]methyl]-2-thiazolyl]guanidine and ethyl 4-bromobenzene-sulfonyl-formimidate is added isopropanol and allowed to crystallize, ebrotidine isopropanolate is obtained, which is a useful intermediate for the preparation of Forms A and B of ebrotidine. Thus, the applicants have found out that Form A of ebrotidine can be obtained in a pure state by treating ebrotidine isopropanolate with a mixture of methanol and water. Treatment of the obtained Form A of ebrotidine with methanol leads to Form B of ebrotidine in a pure state. In turn, if Form B of ebrotidine is preferred to be obtained directly from the methanol solution, which is obtained according to the experimental method in the aforesaid example, the medium may be seeded with crystals of Form B, thus constituing an extremely practical variation.

Forms A and B of ebrotidine have different properties. Form A is an amorphous solid and Form B is a crystalline solid. Therefore, Form A is useful to prepare formulations that do not require any compression, such as capsules or sachets, while Form B is useful to prepare tablets. In case that the formulations to be prepared are liquid, the use of either form will be different since the proper characteristics of the solid state are lost in solution.

Forms A and B of ebrotidine mixed with pharmaceutically acceptable carriers can be administered at daily doses ranging from 50 to 2000 mg.

The following examples illustrate the preparation of Forms A and B of ebrotidine, and pharmaceutical formulations containing them. The examples are not intended to limitate the scope of the invention as defined hereinabove or as claimed below.

EXAMPLE 1 N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide isopropanolate (Ebrotidine isopropanolate)

To a suspension of 44.04 g of [4-[[(2-aminoethyl) thio]methyl]-2-thiazolyl]guanidine dihydrochloride in 100 ml of methanol, 145 ml of 2.05 M methanol potassium hydroxide are added at a temperature below 20° C. To the resultant solution, 42.3 g of ethyl 4-bromobenzene-sulfonyl-formimidate are added at room temperature and the mixture is stirred for 1 hour, cooled at 0-5° C. and filtered. To the filtrate, 245 ml of isopropanol are added at room temperature, and allowed to crystallize for 24 hours to yield 57.9 g of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide isopropanolate having the following physico-chemical properties:

Melting point: 96-98° C.

IR (KBr) cm⁻¹ : 3450 (NH₂), 3380 (NH₂), 1605 (C=N), 1300 (SO₂) and 1180 (SO₂).

¹ H-NMR (DMSO) δ: 1.05 (d, 6H, (CH₃)₂ CH₂ OH), 2.6 (t, 3H, --S--CH₂ --CH₂), 3.4 (m, 2H, --S--CH₂ --CH₂), 3.54 (s, 2H, het--CH₂ --S), 3.8 (m, 2H, (CH₃)₂ CH₂ OH), 6.39 (s, 1H, thiazol), 6.85 (wide, 4H, guanidine), 7.7 (s, 4H, aromatic), 8.15 (s, 1H, NH--CH═N), 9.05 (wide, 1H, --NH--CH═).

EXAMPLE 2 N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromobenzenesulfonamide Form A (Ebrotidine A form)

57.9 g of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide isopropanolate are dissolved in 87 ml of methanol at a temperature ranging between 40 and 50° C. The resultant solution is allowed to stand till a certain degree of turbidness fades away, then filtered and poured onto 550 ml of water at 0-5° C. for 4 hours under energic stirring. After the addition is completed, the mixture is stirred for further 4 hours at 0-5° C. and filtered. The filtrate is washed with abundant water and dried in vacuo at a temperature below 30° C. to yield 49.9 g of ebrotidine Form A.

Melting point: 74-76° C.

IR (KBr) spectrum: FIG. 1

X-ray diffractogram: FIG. 2a.

Differential scanning calorimetry thermogram; FIG. 3.

EXAMPLE 3 N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromobenzenesulfonamide Form B (Ebrotidine Form B)

a) 49.9 g of ebrotidine Form A are poured onto 245 ml of methanol at 30° C. The resultant suspension is heated at 50-60° C. for 1 hour, and then cooled at room temperature and stirred for 2 hours to yield a solid. The solid is filtered to give 41.9 of ebrotidine Form B.

Melting point: 142.5-146° C.

IR (KBr) spectrum: FIG. 4.

X-ray diffractogram: FIG. 2b.

Differential scanning calorimetry thermogram: FIG. 5.

b) To the filtered methanol solution described in Example 1, some crystals of ebrotidine Form B are added and stirred for 24 hours at room temperature to give 37 g of ebrotidine Form B under the same physicochemical properties of section a).

EXAMPLE 4 Monodose sachets

    ______________________________________                                         Ebrotidine Form A      400    mg                                                 Ammonium glycyrrhizinate 120 mg                                                Silicon dioxide 30 mg                                                          Aspartame 20 mg                                                                Corn starch 1600 mg                                                            Scent 80 mg                                                                    Sugar to volume 5000 mg                                                      ______________________________________                                    

EXAMPLE 5 Coated tablets

    ______________________________________                                         Ebrotidine Form B        400    mg                                               Croscarmellose sodium 30 mg                                                    Silicon dioxide 4 mg                                                           Magnesium stearate 12 mg                                                       Talc 60 mg                                                                     Microcrystalline cellulose 30 mg                                               Aminoethylmethacrylate copolymer and 8 mg                                      neutral esters of mathacrylic acid                                             Titanium dioxide 8 mg                                                          Polyethylene glycol 6000 2 mg                                                ______________________________________                                     

We claim:
 1. A compound of the chemical name N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide in Form A having a melting point in the range 74-78° C., the IR spectrum as shown in FIG. 1, the x-ray diffractogram as shown in FIG. 2a and the differential scanning calorimetry thermogram as shown in FIG.
 3. 2. A compound of the chemical name N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide in Form B having a melting point in the range 142.5-146° C., the IR spectrum as shown in FIG. 4, the x-ray diffractogram as shown in FIG. 2b and the differential scanning calorimetry thermogram as shown in FIG.
 5. 3. A process for preparing Form A of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide of claim 1 which comprises reacting [4-[[(2-aminoethyl)thio]methyl]-2-thiazolyl]guanidine dihydrochloride with ethyl 4-bromo-benzene-sulfonylformimidate formimidate in methanol and in the presence of potassium hydroxide, followed by filtering and adding isopropanol over the filtrate to obtain N-[[[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide isopropanolate dissolving in methanol, filtering, and adding to water.
 4. A process for preparing Form B of N-[[[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide of claim 2 which comprises pouring Form A of said compound having a melting point in the range 74-78° C., the IR spectrum as shown in FIG. 1, the x-ray diffractogram as shown in FIG. 2a and the differential scanning calorimetry thermogram as shown in FIG. 3 over methanol; heating the resultant suspension at 50-60° C.; and cooling at room temperature.
 5. A process for preparing Form B of N-[[[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide of claim 2 which comprises seeding crystals of said Form B compound to a filtrate of N-[[[2-[[[2-(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide isopropanolate; and stirring at room temperature. 